Leqembi (lecanemab) works by targeting and clearing toxic clumps of amyloid-beta protein from the brain before they harden into the plaques associated with Alzheimer’s disease. Unlike older approaches that focused on mature, hardened plaques, Leqembi preferentially binds to smaller, soluble protein clusters called protofibrils, which are considered among the most harmful forms of amyloid in the brain. By removing these protofibrils, the drug slows the biological cascade that drives Alzheimer’s progression.
Why Protofibrils Matter
Amyloid-beta is a protein fragment that naturally occurs in the brain. In Alzheimer’s disease, these fragments misfold and stick together, first forming small soluble clusters (protofibrils), then eventually packing into the dense, insoluble plaques visible on brain scans. For years, researchers focused on removing those mature plaques. But growing evidence suggests the earlier-stage protofibrils do more direct damage to brain cells because they circulate freely and interact with neurons in ways that hardened plaques cannot.
Leqembi is an antibody engineered to latch onto these protofibrils with high selectivity. Research from Alzheimer’s disease brain tissue shows that while Leqembi does bind to plaques (both diffuse and compact), it preferentially targets soluble aggregated protofibrils composed largely of a specific form of amyloid called Aβ42. It binds less readily to a different form, Aβ40, which tends to accumulate in blood vessel walls rather than brain tissue. This selectivity matters because it means the drug concentrates its activity where the most neurotoxic protein aggregates are found.
What Happens After the Drug Binds
Once Leqembi locks onto a protofibril, the immune system recognizes the antibody-protein complex as something to clean up. Specialized immune cells in the brain, called microglia, engulf and break down the tagged protofibrils. This clearance process reduces the overall amyloid burden in the brain over time. In clinical trials, participants receiving Leqembi showed significant reductions in brain amyloid levels on PET scans compared to those receiving a placebo, and this suppression of amyloid continued through 36 months of treatment.
How Much It Slows Cognitive Decline
Leqembi does not stop or reverse Alzheimer’s disease. What it does is slow the rate of decline. In the pivotal 18-month Clarity AD trial, participants on Leqembi experienced roughly 27% less cognitive and functional decline compared to placebo, as measured by a scale that tracks memory, judgment, daily activities, and ability to function at home. Long-term extension data through 36 months showed that this benefit continued to accumulate with ongoing treatment. Participants who started Leqembi earlier maintained an advantage over those who started later, and a subgroup with lower overall brain pathology showed stability or even slight improvement between 18 and 36 months.
How Treatment Is Given
Leqembi is administered as an intravenous infusion at a dose based on body weight (10 mg/kg). During the initial phase, infusions are given every two weeks, each lasting about one hour. After stabilization, the schedule shifts to once every four weeks for ongoing maintenance. This means regular visits to an infusion center, which is a significant time commitment for patients and caregivers.
Who Can Receive Leqembi
Not everyone with memory problems is a candidate. Leqembi is approved for people in the early stages of Alzheimer’s disease, specifically those with mild cognitive impairment or mild dementia. Before starting treatment, the presence of amyloid in the brain must be confirmed through either an amyloid PET scan or a cerebrospinal fluid test showing elevated phosphorylated tau and low Aβ42 levels. A clinical diagnosis alone is not sufficient, because some people with Alzheimer’s-like symptoms may not actually have significant amyloid buildup, and the drug would offer no benefit without the target it’s designed to clear.
Genetic testing for a gene variant called APOE ε4 is also recommended before starting treatment. This gene variant, carried by a significant portion of Alzheimer’s patients, affects risk for the drug’s most important side effect. While a positive result doesn’t disqualify someone from treatment, it changes the risk conversation considerably.
ARIA: The Primary Safety Concern
The most significant risk of Leqembi is a set of brain changes known as amyloid-related imaging abnormalities, or ARIA. These come in two forms: brain swelling (ARIA-E) and small brain bleeds (ARIA-H). Most cases are detected on routine MRI scans and cause no symptoms. In the phase 2 trial at the approved dose, about 10% of participants developed brain swelling on imaging, but only 3% experienced symptoms such as headache, confusion, dizziness, or visual changes. Brain microbleeds appeared in about 6% of participants at the same dose.
ARIA risk increases substantially for people who carry two copies of the APOE ε4 gene variant (homozygotes), which accounts for roughly 15% of Alzheimer’s patients. In the phase 3 trial, symptomatic brain swelling occurred in 9.2% of these individuals, compared to 1.7% of those with one copy and 1.4% of those with none. Brain microbleeds of any kind were found in 39% of homozygotes, 14% of those with one copy, and about 12% of non-carriers. These numbers underscore why genetic testing and close monitoring are important parts of the treatment process.
MRI Monitoring During Treatment
Because ARIA can develop without symptoms, the FDA recommends a specific schedule of brain MRI scans during the first year. Patients need a baseline MRI within one year before starting treatment, then additional scans before the 3rd, 5th, 7th, and 14th infusions. For those who carry the APOE ε4 variant, an extra scan at the one-year mark is also recommended. If ARIA is detected, treatment may be paused temporarily until the changes resolve, and in most cases, patients can resume infusions.
This monitoring schedule means frequent imaging appointments on top of infusion visits, which adds to the logistical burden. But it serves a critical function: catching ARIA early, before it progresses or causes symptoms, allows for timely decisions about pausing or adjusting treatment.
What the Drug Does Not Do
Leqembi targets one piece of Alzheimer’s biology. It removes amyloid protofibrils, but Alzheimer’s involves other disease processes, including the buildup of tau tangles inside neurons, chronic brain inflammation, and neuronal death. Once neurons are lost, no current therapy can bring them back. This is why the drug is approved only for early-stage disease: it works best when there is still meaningful brain function to preserve. For people with moderate or advanced Alzheimer’s, the window for this type of treatment has likely passed.